ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation

Sol‐Foulon, Nathalie; Sourisseau, Marion; Porrot, Françoise; Thoulouze, María-Isabel; Trouillet, Céline; Nobile, Cinzia; Blanchet, Fabien P.; Bartolo, Vincenzo Di; Noraz, Nelly; Taylor, Naomi; Alcover, Andrés; Hivroz, Claire; Schwartz, Olivier

doi:10.1038/sj.emboj.7601509

Cited by 107 publications

(116 citation statements)

References 64 publications

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“…rIgG 1 13B8.2 drives the gp120-induced phosphorylation pattern toward a Zap70-negative regulation pathway, explaining why anti-CD4 13B8.2 Ab treatment induces inhibition of NF-B activation and transcription inhibition of the viral genome, whereas gp120 binding leads to NF-B activation and productive transcription of the viral genome in the case of HIV infection (23). Of great interest is that Zap70 is required in infected donor cells for efficient cell-tocell HIV transmission to recipients and for formation of the virological synapse (58 (57). Tyr 319 residue is autophosphorylated in vitro and becomes phosphorylated in vivo upon TCR triggering (56), leading to positive regulation of TCR-mediated signaling.…”

Section: Discussionmentioning

confidence: 99%

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Chentouf

Ghannam

Bès

et al. 2007

The Journal of Immunology

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The biological effects of rIgG1 13B8.2, directed against the CDR3-like loop on the D1 domain of CD4, are partly due to signals that prevent NF-κB nuclear translocation, but the precise mechanisms of action, particularly at the level of membrane proximal signaling, remain obscure. We support the hypothesis that rIgG1 13B8.2 acts by interfering with the spatiotemporal distribution of signaling or receptor molecules inside membrane rafts. Upon cross-linking of Jurkat T lymphocytes, rIgG1 13B8.2 was found to induce an accumulation/retention of the CD4 molecule inside polyoxyethylene-20 ether Brij 98 detergent-resistant membranes at 37°C, together with recruitment of TCR, CD3ζ, p56 Lck, Lyn, and Syk p70 kinases, linker for activation of T cells, and Csk-binding protein/phosphoprotein associated with glycosphingolipid adaptor proteins, and protein kinase Cθ, but excluded Zap70 and its downstream targets Src homology 2-domain-containing leukocyte protein of 76 kDa, phospholipase Cγ1, and p95vav. Analysis of key upstream events such as Zap70 phosphorylation showed that modulation of Tyr292 and Tyr319 phosphorylation occurred concomitantly with 13B8.2-induced Zap70 exclusion from the membrane rafts. 13B8.2-induced differential raft partitioning was epitope, cholesterol, and actin dependent but did not require Ab hyper-cross-linking. Fluorescence confocal imaging confirmed the spatiotemporal segregation of the CD4 complex inside rafts and concomitant Zap70 exclusion, which occurred within 10–30 s following rIgG1 13B8.2 ligation, reached a plateau at 1 min, and persisted until the end of the 1-h experiment. The differential spatiotemporal partitioning between the CD4 receptor and the Zap70-signaling kinase inside membrane rafts interrupts the proximal signal cross-talk leading to subsequent NF-κB nuclear translocation and explains how baculovirus-expressed CD4-CDR3-like-specific rIgG1 13B8.2 acts to induce its biological effects.

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Section: Discussionmentioning

confidence: 99%

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Chentouf

Ghannam

Bès

et al. 2007

The Journal of Immunology

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“…Jurkat cells, J␤2.7 cells, phytohemagglutinin-activated human primary CD4 T lymphocytes, or monocyte-derived dendritic cells (DCs) were infected with HIV [NL4-3 for lymphocytes, NL4-3(VSV) pseudotypes for DCs] or a ⌬env mutant derivative as described previously (48,49). Jurkat derivative J␤2.7 cells (which lack LFA-1) and J␤2.7-LFA1 ϩ cells (in which LFA-1 expression was restored) were a kind gift from Catarina Hioe (15).…”

Section: Cells and Virusesmentioning

confidence: 99%

Simultaneous Cell-to-Cell Transmission of Human Immunodeficiency Virus to Multiple Targets through Polysynapses

Rudnicka

Feldmann

Porrot

et al. 2009

J Virol

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204

267

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Human immunodeficiency virus type 1 (HIV-1) efficiently propagates through cell-to-cell contacts, which include virological synapses (VS), filopodia, and nanotubes. Here, we quantified and characterized further these diverse modes of contact in lymphocytes. We report that viral transmission mainly occurs across VS and through "polysynapses," a rosette-like structure formed between one infected cell and multiple adjacent recipients. Polysynapses are characterized by simultaneous HIV clustering and transfer at multiple membrane regions. HIV Gag proteins often adopt a ring-like supramolecular organization at sites of intercellular contacts and colocalize with CD63 tetraspanin and raft components GM1, Thy-1, and CD59. In donor cells engaged in polysynapses, there is no preferential accumulation of Gag proteins at contact sites facing the microtubule organizing center. The LFA-1 adhesion molecule, known to facilitate viral replication, enhances formation of polysynapses. Altogether, our results reveal an underestimated mode of viral transfer through polysynapses. In HIV-infected individuals, these structures, by promoting concomitant infection of multiple targets in the vicinity of infected cells, may facilitate exponential viral growth and escape from immune responses.

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“…Although these and similar experiments with other kinds of cell-cell synapses (14,15) have provided informative glimpses of the nature of cell-cell contact, imaging experiments using conventional 2D TEM provide only crosssectional views. The focus of the experiments presented here is to describe the 3D architecture of virological synapses using two emerging technologies for 3D electron microscopy: ion abrasion (IA) SEM (16,17) and electron tomography (18).…”

mentioning

confidence: 99%

3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

Felts

Narayan

Estes

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

169

176

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The efficiency of HIV infection is greatly enhanced when the virus is delivered at conjugates between CD4 + T cells and virus-bearing antigen-presenting cells such as macrophages or dendritic cells via specialized structures known as virological synapses. Using ion abrasion SEM, electron tomography, and superresolution light microscopy, we have analyzed the spatial architecture of cell-cell contacts and distribution of HIV virions at virological synapses formed between mature dendritic cells and T cells. We demonstrate the striking envelopment of T cells by sheet-like membrane extensions derived from mature dendritic cells, resulting in a shielded region for formation of virological synapses. Within the synapse, filopodial extensions emanating from CD4 + T cells make contact with HIV virions sequestered deep within a 3D network of surface-accessible compartments in the dendritic cell. Viruses are detected at the membrane surfaces of both dendritic cells and T cells, but virions are not released passively at the synapse; instead, virus transfer requires the engagement of T-cell CD4 receptors. The relative seclusion of T cells from the extracellular milieu, the burial of the site of HIV transfer, and the receptor-dependent initiation of virion transfer by T cells highlight unique aspects of cell-cell HIV transmission.

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ZAP-70 kinase regulates HIV cell-to-cell spread and virological synapse formation

Cited by 107 publications

References 64 publications

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Recombinant Anti-CD4 Antibody 13B8.2 Blocks Membrane-Proximal Events by Excluding the Zap70 Molecule and Downstream Targets SLP-76, PLCγ1, and Vav-1 from the CD4-Segregated Brij 98 Detergent-Resistant Raft Domains

Simultaneous Cell-to-Cell Transmission of Human Immunodeficiency Virus to Multiple Targets through Polysynapses

3D visualization of HIV transfer at the virological synapse between dendritic cells and T cells

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